Endothelium-derived hydrogen sulfide acts as a hyperpolarizing factor and exerts neuroprotective effects via activation of large-conductance Ca 2+ -activated K + channels.

Background and Purpose: Endothelium-derived hyperpolarizing factor (EDHF) has been suggested as a therapeutic target for vascular protection against ischaemic brain injury. However, the molecular entity of EDHF and its action on neurons remains unclear. This study was undertaken to demonstrate whether the hydrogen sulfide (H ₂ S) acts as EDHF and exerts neuroprotective effect via large-conductance Ca ²⁺ -activated K ⁺ (BK _Ca /K _Ca 1.1) channels.
Experimental Approach: The whole-cell patch-clamp technology was used to record the changes of BK _Ca currents in rat neurons induced by EDHF. The cerebral ischaemia/reperfusion model of mice and oxygen-glucose deprivation/reoxygenation (OGD/R) model of neurons were used to explore the neuroprotection of EDHF by activating BK _Ca channels in these neurons.
Key Results: Increases of BK _Ca currents and membrane hyperpolarization in hippocampal neurons induced by EDHF could be markedly inhibited by BK _Ca channel inhibitor iberiotoxin or endothelial H ₂ S synthase inhibitor propargylglycine. The H ₂ S donor, NaHS-induced BK _Ca current and membrane hyperpolarization in neurons were also inhibited by iberiotoxin, suggesting that H ₂ S acts as EDHF and activates the neuronal BK _Ca channels. Besides, we found that the protective effect of endothelium-derived H ₂ S against mice cerebral ischaemia/reperfusion injury was disrupted by iberiotoxin. Importantly, the inhibitory effect of NaHS or BK _Ca channel opener on OGD/R-induced neuron injury and the increment of intracellular Ca ²⁺ level could be inhibited by iberiotoxin but enhanced by co-application with L-type but not T-type calcium channel inhibitor.
Conclusion and Implications: Endothelium-derived H ₂ S acts as EDHF and exerts neuroprotective effects via activating the BK _Ca channels and then inhibiting the T-type calcium channels in hippocampal neurons.
(© 2021 The British Pharmacological Society.)